{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T01:32:15Z","timestamp":1774661535737,"version":"3.50.1"},"reference-count":0,"publisher":"Rockefeller University Press","issue":"4","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1996,10,1]]},"abstract":"<jats:p>Among the anti-neutrophil cytoplasmic antibodies (ANCA), those targeting proteinase 3 (PR3) have a high specificity for Wegener's granulomatosis (WG). It is known that a preceding priming of neutrophils with cytokines is a prerequisite for membrane surface expression of PR3, which is then accessible to autoantibody binding. Employing a monoclonal antibody directed against human PR3 and ANCA-positive serum from WG patients with specificity for PR3, we now investigated the role of free arachidonic acid (AA) in autoantibody-related human neutrophil activation. Priming of neutrophils with tumor necrosis factor (TNF-alpha) for 15 min or exposure to anti-PR3 antibodies or incubation with free AA (10 microM) as sole events did not provoke superoxide generation, elastase secretion or generation of 5-lipoxygenase products of AA. Similarly, the combination of TNF-alpha-priming and AA incubation was ineffective. When TNF-alpha-primed neutrophils were stimulated by anti-PR3 antibodies, superoxide and elastase secretion was provoked in the absence of lipid mediator generation. However, when free AA was additionally provided, a strong activation of the 5-lipoxygenase pathway was demasked, with the appearance of excessive quantities of leukotriene (LT)B4, LTA4, and 5-hydroxyeicosatetraenoic acid. Moreover, superoxide and elastase secretion were markedly amplified, and studies with 5-lipoxygenase inhibitors and a LTB4-antagonist demonstrated this was due to an LTB4-related autocrine loop of cell activation. In contrast, the increased synthesis of platelet-activating factor in response to TNF-alpha-priming and anti-PR3 stimulation did not contribute to the amplification loop of neutrophil activation under the given conditions. We conclude that anti-PR3 antibodies are potent inductors of the 5-lipoxygenase pathway in primed human neutrophils, and extracellular free AA, as provided at an inflammatory focus, synergizes with the autoantibodies to evoke full-blown lipid mediator generation, granule secretion and respiratory burst. Such events may be enrolled in the pathogenesis of focal necrotizing vascular injury in Wegener's granulomatosis.<\/jats:p>","DOI":"10.1084\/jem.184.4.1567","type":"journal-article","created":{"date-parts":[[2004,6,24]],"date-time":"2004-06-24T07:56:10Z","timestamp":1088063770000},"page":"1567-1572","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":46,"title":["Neutrophil activation by anti-proteinase 3 antibodies in Wegener's granulomatosis: role of exogenous arachidonic acid and leukotriene B4 generation."],"prefix":"10.1084","volume":"184","author":[{"given":"F","family":"Grimminger","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K","family":"Hattar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Papavassilis","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B","family":"Temmesfeld","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E","family":"Csernok","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W L","family":"Gross","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W","family":"Seeger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"U","family":"Sibelius","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[1996,10,1]]},"container-title":["The Journal of experimental medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/184\/4\/1567\/1679260\/1567.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/184\/4\/1567\/1679260\/1567.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T07:23:32Z","timestamp":1690269812000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/184\/4\/1567\/51171\/Neutrophil-activation-by-anti-proteinase-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1996,10,1]]},"references-count":0,"journal-issue":{"issue":"4","published-print":{"date-parts":[[1996,10,1]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.184.4.1567","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[1996,10,1]]}}}